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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene.
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Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene.

机译：维拉帕米暴露于甲苯的大鼠的动力学处置和代谢中的对映选择性降低。

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摘要

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal-Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng x h x mL(-1); p < or = 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng x h x mL(-1); p < or = 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.
机译：甲苯和维拉帕米易受CYP酶介导的广泛氧化代谢的影响，它们之间的相互作用可能是立体选择性的。在本研究中，我们调查了甲苯吸入对大鼠中维拉帕米及其代谢产物诺维拉帕米对映选择性动力学处置的影响。雄性Wistar大鼠（每组n = 6）在仅鼻涕甲苯或空气吸入的第五天（对照组）口服单剂量消旋维拉帕米（10 mg / kg），每天吸入6 h（25、50，和100 ppm）。维拉帕米给药后直至6小时，均从尾部采集系列血样。使用Chiralpak AD色谱柱通过LC-MS / MS分析维拉帕米和降维拉帕米对映体的血浆浓度。吸入甲苯不会影响大鼠中维拉帕米或去甲维拉帕米对映体的动力学分布（p> 0.05，Kruskal-Wallis试验）。对照组中维拉帕米的药动学具有对映体选择性，S-维拉帕米的血浆比例较高（AUC 250.8对120.4 ng xhx mL（-1）; p <或= 0.05，Wilcoxon试验）和S-去甲维拉帕米（AUC 72.3）对比52.3 ng xhx mL（-1）; p <或= 0.05，Wilcoxon检验）。仅鼻子暴露于25、50或100 ppm的甲苯会导致维拉帕米和去甲维拉帕米均缺乏对映选择性。该研究证明了对映选择性方法在溶剂与手性药物之间相互作用研究中的重要性。

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